Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics

ABSTRACT

The invention relates to tetrahydroisoquinoline sulfonamide compounds (of formula (1) as defined in the specification), their preparation and their use in therapies for the treatment of central nervous system diseases such as vigilance and sleep disorders, narcolepsy, Alzheimer&#39;s disease and other dementias, Parkinson&#39;s disease, attention disorders in hyperkinetic children, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety, sexual dysfunction, dizziness and travel sickness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/FR2005/001279, filed May 24,2005, which claims priority from FR Patent Application No. 04,05,607,filed May 25, 2004.

SUMMARY OF THE INVENTION

The present invention relates to sulfonamide derivatives, to thepreparation thereof and to the therapeutic use thereof, in particular inthe treatment of disorders that are improved by modulation of thehistamine H₃ receptor, such as obesity, diabetes and central nervoussystem diseases such as vigilance and sleep disorders.

DETAILED DESCRIPTION OF THE INVENTION

Consequently, a first subject of the present invention is the compoundscorresponding to formula I

in which:

n can represent a value between 1 and 6;

—(C)n- represents a —C₁₋₆ alkylidene group optionally substituted with 1to 4 substituents chosen from a halogen atom, and a hydroxyl, nitro,cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino or C₁₋₃ alkoxygroup;

R1 represents

-   -   a hydrogen atom,    -   a C₁₋₆ alkyl group;

R2 represents

-   -   a hydrogen atom,    -   a C₁₋₆ alkyl or C₃₋₆ cycloalkyl group optionally substituted        with 1 to 4 substituents chosen from a halogen atom, a hydroxyl,        nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino,        C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy or C₃₋₆        cycloalkyl group, a monocyclic heteroaryl such as a thienyl,        furyl or pyrrolyl, or an aryl, such as a phenyl or a naphthyl;        the aryl being optionally substituted with 1 to 4 substituents        chosen from a halogen atom, a hydroxyl, nitro, cyano, amino,        C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl, C₁₋₂        perhaloalkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy group or a C₁₋₃        alkylidenedioxy group;

B represents

-   -   NR3R4,        -   R3 and R4 represent, independently of one another, a C₁₋₆            alkyl group, or a hydrogen atom; or        -   R3 and R4 together represent a C₁₋₆ alkylidene group, a C₂₋₈            alkenylidene group, a C₁₋₃ alkylidene-O—C₁₋₃ alkylidene            group, or a C₁₋₃ alkylidene-N(R5)—C₁₋₃ alkylidene group            where R5 represents a hydrogen atom, or a C₁₋₃ alkyl or C₁₋₆            alkylcarbonyl group, it being possible for these C₁₋₃ alkyl            and C₁₋₆ alkylcarbonyl groups to be substituted with a            halogen atom, or a hydroxyl, C₁₋₃ alkoxy, nitro, cyano or            amino group; or    -   an aminocycle, linked via a carbon to the group —NR1—(C)n-, such        as aziridine, azetidine, pyrrolidine, piperidine or morpholine;        the groups R3 and R4 and also the aminocycle being optionally        substituted with 1 to 4 substituents chosen from a phenyl, a        benzyl, a halogen atom, and a hydroxyl, nitro, cyano, amino,        C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl or C₁₋₃        alkoxy group; and the nitrogen atom optionally substituted with        a C₁₋₃ alkyl.

In the context of the present invention, the term:

-   -   “C_(x-z)” is intended to mean a carbon-based chain that may        contain from x to z carbon atoms; for example, C₁₋₃ indicates a        carbon-based chain that may contain from 1 to 3 carbon atoms;    -   “alkyl” is intended to mean a linear or branched, saturated        aliphatic group; for example, a C₁₋₄ alkyl group represents a        linear or branched, saturated carbon-based chain containing from        1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, tert-butyl, etc. radical; the term        “C_(x-y) alkylidene” denoting a divalent, linear or branched        C_(x-y) alkyl group; the term “C₂₋₈ alkenylidene” denoting a        divalent, linear or branched, unsaturated C_(x-y) alkyl group;    -   “C_(x-y) alkoxy” is intended to mean an alkyloxy group        comprising a linear or branched, saturated aliphatic chain,        containing x to y carbon atoms;    -   “halogen atom” is intended to mean a fluorine, a chlorine, a        bromine or an iodine;    -   “C₁₋₃ monoalkylamino” is intended to mean an amino        monosubstituted with a C₁₋₃ alkyl group;    -   “C₂₋₆ dialkylamino” is intended to mean an amino disubstituted        with two C₁₋₃ alkyl groups;    -   “C₁₋₂ perhaloalkyl” is intended to mean a C₁₋₂ alkyl group in        which all the hydrogen atoms are substituted with halogen atoms;    -   “C₁₋₃ haloalkyl” is intended to mean a C₁₋₃ alkyl group in which        at least one hydrogen atom is substituted with a halogen atom.

The compounds of formula I can contain one or more asymmetrical carbonatoms. They can therefore exist in the form of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, are part of the invention.

The compounds of general formula I can be in the form of free bases orof addition salts with acids, which are also part of the invention.According to the present invention, these salts comprise those withpharmaceutically acceptable acids, but also those with inorganic ororganic acids that allow a suitable separation or crystallization of thecompounds of formula I. These salts can be prepared, according tomethods known to those skilled in the art, for example, by reaction ofthe compound of formula I in the form of a base with the acid in anappropriate solvent, such as an alcoholic solution or an organicsolvent, and then separation of the media that contains it byevaporation of the solvent or by filtration.

The compounds of formula I can also exist in the form of hydrates or ofsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates arealso part of the invention.

Furthermore, in the context of the present invention, the term“protective group Pg” is intended to mean a group that makes itpossible, firstly, to protect a reactive function such as a hydroxyl oran amine during a synthesis and, secondly, to regenerate the intactreactive function at the end of synthesis. Examples of protective groupsand also the methods of protection and deprotection are given in“Protective groups in Organic Synthesis 3^(rd) Ed.”, Greene and Wuts(John Wiley & Sons, Inc., New York, 1999).

A subject of the present invention is also the compounds chosen from thefollowing subgroups, in which:

-   -   n is equal to 2, 3 or 4; and/or    -   R1 represents a hydrogen atom or a C₁₋₂ alkyl group; and/or    -   R2 represents a hydrogen atom, or a C₁₋₄ alkyl or C₅₋₆        cycloalkyl group optionally substituted with 1 to 4 substituents        chosen from a phenyl, and a C₃₋₆ cycloalkyl, C₁₋₂ perhaloalkyl,        C₁₋₃ haloalkyl or C₁₋₃ alkoxy group; the phenyl being optionally        substituted with 1 to 4 substituents chosen from a halogen atom,        a hydroxyl, nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆        dialkylamino, C₁₋₃ alkyl, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl or        C₁₋₃ alkoxy group or a C₁₋₃ alkylidenedioxy group; and/or    -   B represents        -   NR3R4,            -   R3 and R4 represent, independently of one another, a                C₁₋₄alkyl group; or            -   when R3 and R4 together represent a C₁₋₆ alkylidene                group, a C₂₋₈ alkenylidene group, a C₁₋₃                alkylidene-O—C₁₋₃ alkylidene group or a C₁₋₃                alkylidene-N(R5)-C₁₋₃ alkylidene group, B represents a                group:

-   -   or        -   an aminocycle linked via a carbon to the group —NR1-(C)n,            such as aziridine, azetidine, pyrrolidine, piperidine or            morpholine;            the groups R3, R4 and R5 and also the aminocycle being            optionally substituted; and, more specifically, the subgroup            where at the same time n, R1, R2 and B are as defined above.

More particularly, when B represents NR3R4 and R3 and R4 together form aC₁₋₆ alkylidene group, a C₂₋₈ alkenylidene group, a C₁₋₃alkylidene-O—C₁₋₃ alkylidene group or a C₁₋₃ alkylidene-N(R5)-C₁₋₃alkylidene group, or when B represents an aminocycle, then B is chosenfrom the following groups:

Another subject of the present invention concerns the followingcompounds:

-   1.    N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   2.    (+/−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   3.    N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   4.    N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   5.    2-benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   6.    2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   7.    2-(cyclohexylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   8.    (+/−)-N-[3-(2-methylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   9.    N-[3-(3,6-dihydropyridin-1(2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   10.    N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   11.    N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   12.    N-[3-(diethylamino)propyl]-2-(3-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   13.    N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   14.    2-cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   15.    (+/−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

16.N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

-   17.    N-[3-(4-benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   18.    N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   19.    N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   20.    N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   21.    2-(cyclohexylmethyl)-N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   22.    (+/−)-2-(cyclopropylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   23.    (+/−)-2-benzyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   24.    (+/−)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   25.    (+/−)-2-(1,3-benzodioxol-5-ylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   26.    (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   27.    (−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   28.    (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   29.    (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;-   30.    (+/−)-2-(4-bromobenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide-   31.    (+/−)-2-(2,5-dimethoxybenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide-   32.    (+/−)-2-(2-methylbutyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide-   33. (+/−)-2-(3-methoxybenzyl)-N-[2-(1-methyl    pyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide    and-   34.    (+/−)-2-(3,5-dimethyl-benzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide.

A second subject of the present invention is processes for preparing thecompounds of formula I according to the invention.

Thus, the compounds of formula I can be prepared according to theprocess represented in Scheme 1.

According to the process of Scheme 1, the compounds of formula I, inwhich R2 is other than a hydrogen atom, are prepared by amminativereduction, by reacting a secondary amine of formula I, in which R2represents H, with an aldehyde or a ketone of formula III, where R6 andR7, after reaction, together form R2 as defined in formula I. Thecompounds of formula I where R2 represents a hydrogen atom can beobtained by deprotection of the compounds of formula II, according toconventional methods known to those skilled in the art. For example, thecompounds of formula II, when Pg is a trifluoroacetyl group, can bedeprotected in the presence of a base such as, for example, sodiumcarbonate, potassium carbonate, ammonia or barium hydroxide in a proticsolvent, such as water or methanol or a mixture of these solvents, at atemperature between 0 and 100° C. Alternatively, the deprotection of thecompounds of formula II, when Pg is a trifluoroacetyl group, can becarried out in the presence of an acid such as, for example,hydrochloric acid in a protic or aprotic solvent, such as water,methanol, ethanol or ethyl acetate or a mixture of these solvents, at atemperature between 0 and 100° C. Illustrations of the process are givenin the examples.

The starting compounds of formula II can be prepared according to Scheme2 or can be synthesized by conventional methods known to those skilledin the art.

According to this scheme, the compounds of formula II, in which n, R1and B are as defined in formula I, can be prepared by reaction of anamine of formula V, in which R1 and B are as defined in formula I, witha sulfonyl chloride of formula IV, in which Pg represents an appropriateprotective group such as, for example, a trifluoroacetamide, so as toform a derivative of sulfonamide type of formula II, according toconventional methods known to those skilled in the art, for example, thereaction can be carried out in a protic or aprotic solvent, such astetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamideor acetonitrile or a mixture of these solvents, at a temperature ofbetween 0 and 100° C., in the presence of a base such as, for example,potassium carbonate, sodium carbonate, diisopropylethylamine ortriethylamine.

Alternatively, the compounds of formula II can be prepared by aMitsunobu type reaction, according to Scheme 3.

According to this alternative, a sulfonamide of formula VII, in which R1is as defined in formula I, is reacted with an amino alcohol of formulaVIII, in which n and B are as defined above. The reaction can be carriedout conventionally in the presence of Mitsunobu reagents, such as an azoderivative, for example diethylazodicarboxylate,diisopropylazodicarboxylate, di-tert-butylazodicarboxylate,1,1′-(azodicarbonyl)dipiperidine or N,N,N′,N′tetramethylazodicarboxamide, and a phosphine, for exampletriphenylphosphine or tributylphosphine. The reaction can be carried outin an aprotic solvent, such as tetrahydrofuran or dioxane or a mixtureof these solvents, at a temperature between 0 and 100° C., to give thecompound of formula II. The sulfonamide of formula VII in which R1 is asdefined in formula I can be prepared by reaction of an amine of formulaVI, in which R1 is as defined in formula I, with a sulfonyl chloride offormula IV, in which Pg represents an appropriate protective group suchas, for example, a trifluoroacetamide, according to conventional methodsknown to those skilled in the art, for example, the reaction can becarried out in a protic or aprotic solvent, such as tetrahydrofuran,dichloromethane, ethyl acetate, Ia N,N-dimethylformamide or acetonitrileor a mixture of these solvents, at a temperature between 0 and 100° C.,in the presence of a base such as, for example, potassium carbonate,sodium carbonate, diisopropylethylamine or triethylamine.

The starting compounds IV and the amines of formulae V and VIII aredirectly commercially available, can be synthesized by conventionalmethods known to those skilled in the art, or are known in theliterature.

For example, the diamines of formula V, in which n is equal to 3, can beprepared according to Scheme 4.

According to this process, the compounds of formula V, in which n isequal to 3, R1 represents a hydrogen atom and B represents an aminegroup, can be prepared by means of an addition reaction of an amine offormula X, in which R3 and R4 are as defined above, with theacrylonitrile of formula IX, so as to form a derivative of aminonitriletype of formula XI, according to conventional methods known to thoseskilled in the art, followed by reduction of the nitrile. The reductioncan be carried out according to methods known to those skilled in theart, for example in the presence of diisobutylaluminum hydride at atemperature between −70° C. and 40° C. in an aprotic solvent such asdichloromethane or toluene or a mixture of these solvents; the reductioncan also be carried out in the presence of a reducing agent, such ashydrogen, in the presence of a catalyst such as platinum, palladium orRaney nickel, in a solvent such as methanol or ethyl acetate, so as togive the compound of formula V, in which n is equal to 3, R1 representsa hydrogen atom and B represents an amine group. The compounds offormula V, in which R1 represents a C₁₋₆ alkyl group, can be prepared byalkylation of the compound of formula V obtained above, according toconventional methods known to those skilled in the art.

A subject of the present invention is also the compounds of formula II,when Pg represents a protective group or a hydrogen atom, asintermediates for the preparation of the compound of formula I.

The following examples illustrate the processes and techniques suitablefor the preparation of this invention, without, however, limiting thescope of the claim.

EXAMPLE 1N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

1.1-(+/−)-N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

A solution of 5.00 g (0.015 mol) of2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonylchloride and 2.00 g (0.015 mol) of(+/−)-2-(1-methyl-pyrrolidin-2-yl)-ethylamine, in 50 ml ofdichloromethane, is stirred overnight at ambient temperature. Thesolution is concentrated to dryness. The solid formed is purified bysilica gel column chromatography, with a dichloromethane/methanol (97:3)mixture used as eluant, to give 4.30 g of the desired product in theform of a white solid.

Yield: 62%

Mp=amorphous

1.2-(+/−)-N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

A solution of 4.30 g (0.0094 mol) of2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamido-[2-(1-methylpyrrolidin-2-yl)ethyl]hydrochloride in 50 ml of methanol saturated with hydrogen chloride isheated for twelve hours at 60° C. The mixture is cooled and the solidthat has formed is filtered off, washed with methanol and dried. 2.00 gof the desired product are obtained as a white solid.

Yield: (65%)

Mp=209-212° C.

¹H-NMR (DMSO-d₆)δ(ppm): 7.9 (1H, t), 7.7 (2H, d), 7.5 (1H, d), 4.3 (2H,s), 3.6 (5H, m), 3.1 (3H, m), 2.9 (2H, m), 2.7 (3H, m), 2.1 (1H, m), 1.9(3H, m), 1.6 (2H, m) 2.7 (3H, s); 2.9 (2H, t).

1.3-(+) or(−)-N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

The compound obtained above in 1.2 is separated by chiral-phasepreparative chromatography, to give its enantiomers. Specifically, theseparation of 15.00 g of(+/−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride is carried out with a PROCHROM LC50 preparative HPLCsystem, with a CHIRALPACK AD stationary phase and a mobile phase formedfrom isohexane/ethanol/methanol (80%:10%:10%)+0.2% of diethylamine, togive 5.39 g of the dextrorotatory product, in the form of a whitepowder, with a chiral-phase enantiomeric purity of 99.67%, and 4.89 g ofthe levorotatory product, in the form of a white solid, with achiral-phase enantiomeric purity of 99.48%. The two products areconverted into their corresponding hydrochloride by a treatment withisopropanol saturated with hydrogen chloride.

-   -   Dextrorotatory enantiomer: Mp=114-117° C.; [α]_(D) ²⁰=+16        (c=0.5, methanol)    -   Levorotatory enantiomer: Mp=115-117° C.; [α]_(D) ²⁰=−16 (c=0.5,        methanol)

EXAMPLE 2(+/−)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideoxalate (1:2)

0.32 g (0.0003 mol) of palladium-on-charcoal at 10% is added to asolution of 2.02 g (0.0063 mol) of(+/−)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamido-[2-(1-methyl-pyrrolidin-2-yl)ethyl]and 0.70 g (0.0063 mol) of cyclohexanecarboxaldehyde in 100 ml ofmethanol. The solution is hydrogenated for 24 hours in a Paarhydrogenator at a pressure of 45 Psi. The catalyst is removed byfiltration and the filtered solution is evaporated to dryness. The crudeoil obtained (2.90 g) is purified by silica gel column chromatography,with a dichloromethane/methanol (95:5) mixture used as eluant. Thedesired product (1.62 g; 62%) is obtained in the form of an oil.

The above oil is dissolved in 20 ml of ethanol, and then 0.77 g (0.0086mol) of oxalic acid dissolved in 15 ml of ethanol is added. Theprecipitate is filtered off and washed with cold ethanol. 2.01 g of thedesired product are obtained in the form of a white solid.

Yield: 86%

Mp=142-147° C.

¹H-NMR (DMSO-d₆)δ(ppm): 7.5 (2H, m), 7.29 (1H, m), 3.84 (2H, s), 3.35(2H, m), 3.1 (1H, m), 2.9 (1H, m), 2.8 (2H, s), 2.7 (1H, m), 2.6 (3H,s), 2.5 (2H, m), 2.1-1.4 (13H, m), 1.15 (4H, m), 0.8 (2H, m).

EXAMPLE 3(+)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideoxalate (1:1.5)

According to a process similar to Example 2, with 1.00 g (0.0031 mol) of(+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideand 0.35 g (0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml ofmethanol as starting product, 0.46 g of base is obtained, which base isconverted into the corresponding sesquioxalate hydrate, as a whitesolid.

Yield: 20%

Mp=134-140° C.

[α]_(D) ²⁰=+12 (c=0.5, methanol)

EXAMPLE 4(−)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideoxalate (1:2)

According to a process similar to Example 2, with 1.00 g (0.0031 mol) of(−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideand 0.35 g (0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml ofmethanol as starting product, 0.90 g of base is obtained, which base isconverted into the corresponding dioxalate hydrate, as a white solid.

Yield: 27%

Mp=133-138° C.

[α]_(D) ²⁰=−8 (c=0.5, methanol)

EXAMPLE 52-Benzyi-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideoxalate (1:2)

5.1-N-[2-(3-Diethylaminopropyl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

A solution of 1.00 g (0.0031 mol) of2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonylchloride and 0.61 g (0.0047 mol) of N,N-diethyl-N-aminopropylamine in 25ml of dichloromethane is stirred overnight at ambient temperature. Thesolution is concentrated to dryness and the oil formed is purified bysilica gel column chromatography, with a dichloromethane/methanol (97:3)mixture used as eluant. 1.27 g are obtained.

Yield: 97%

Mp=Oil

5.2-N-[3-(Diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

A solution of 5.39 g (0.013 mol) ofN-[2-(3-diethylaminopropyl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride, dissolved in 60 ml of methanol saturated with hydrogenchloride, is heated for twelve hours at 60° C. The mixture is cooled andthe solid that has formed is filtered off, washed with methanol anddried. The residue is dissolved in an aqueous solution of sodiumhydroxide. The aqueous phase is extracted several times with ethylether. The organic phases are combined and dried over anhydrousmagnesium sulfate. The oil obtained (2.80 g) is used without additionalpurification.

Yield: 67%

Mp=Oil

5.3-2-Benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideoxalate (1:2)

1.5 ml of acetic acid are added to a suspension of 0.45 g (0.0014 mol)ofN-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideand 0.149 g (0.0014 mol) of benzaldehyde in 12 ml of tetrahydrofuran.The suspension is stirred for 1 hour at ambient temperature and then0.14 g (0.0021 mol) of sodium cyanoborohydride was added. The mixturewas stirred overnight. The mixture is concentrated to dryness and theresidue is treated with water and washed with ethyl ether. The aqueousphase is basified to pH=10 and is extracted several times with ethylether. The organic phases are combined and dried over anhydrousmagnesium sulfate. The oil obtained is purified by silica gel columnchromatography, with a dichloromethane/methanol (95:5) mixture used aseluant. The desired product (0.13 g; 22%) is obtained in the form of anoil.

The above oil is dissolved in 5 ml of ethanol, and then 0.06 g (0.0007mol) of oxalic acid, dissolved in 5 ml of ethanol, is added. Theprecipitate is filtered off and washed with cold ethanol. 0.12 g of thedesired product is obtained as a white solid.

Yield: 63%

Mp=91-103° C.

¹H-NMR (DMSO-d₆)δ(ppm): 7.5-7.1 (8H, m), 3.52 (2H, d), 2.9-2.5 (14H, m),1.5 (2H, m), 0.9 (6H, t).

EXAMPLE 6N-[3-(Diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidehydrochloride

6.1-N-[2-(3-Diethylaminopropyl)-N-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

0.09 g (0.0022 mol) of a dispersion of sodium hydride (60%) in a mineraloil is added to a solution of 0.91 g (0.0021 mol) ofN-[2-(3-diethylaminopropyl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide(obtained according to the method described in stage 5.1- of Example 5)in 17 ml of dimethylformamide, cooled to 0° C. The mixture is stirredfor one hour and 0.60 g (0.0042 mol) of methyl iodide is added. Themixture is stirred overnight at ambient temperature, and the solution isconcentrated to dryness. The residue is treated with water. The aqueousphase is extracted several times with ethyl acetate. The organic phasesare combined and dried over anhydrous magnesium sulfate. The oilobtained after filtration and evaporation of the solvent is purified bysilica gel column chromatography, with a dichloromethane/methanol (95:5)mixture used as eluant, to give 0.31 g of the desired product in theform of an oil.

Yield: 34%

Mp=Oil

6.2-N-[2-(3-Diethylaminopropyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

To a solution of 0.20 g (0.00046 mol) ofN-[2-(3-diethylaminopropyl)-N-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamidedissolved in 10 ml of methanol saturated with hydrogen chloride isheated for twelve hours at 60° C. The solution is concentrated todryness and the residue is treated with water. The aqueous phase isextracted several times with ethyl ether. The organic phases arecombined and dried over anhydrous magnesium sulfate, and the solution isconcentrated to dryness, to give 0.02 9 of the desired product in theform of an oil.

Yield: 12%

Mp=Oil

¹H-NMR (DMSO)δ(ppm): 9.67 (1H, s, NH), 7.7 (1H, s), 7.68 (1H, d), 7.5(1H, d), 4.4 (2H, s), 3.5-2.9 (12H, m), 2.7 (3H, s), 1.9 (2H, m), 1.15(6H, t).

EXAMPLE 72-Cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideethanodioate (1:1)

5 ml of acetic acid are added to a suspension of 1.70 g (0.0050 mol) ofN-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide(obtained according to the method described in stage 3.2- of Example 3)and 0.98 g (0.0014 mol) of cyclohexanone in 50 ml of tetrahydrofuran.The mixture is stirred for 3 hours at ambient temperature and 0.47 g(0.0075 mol) of sodium cyanoborohydride is added. The mixture is stirredovernight. The mixture is concentrated to dryness. The residue istreated with water and washed with ethyl ether. The aqueous phase isbasified to pH=10 and is extracted several times with ethyl ether. Theorganic phases are combined and dried over anhydrous magnesium sulfate.The oil obtained is purified by silica gel column chromatography, with adichloromethane/methanol (95:5) mixture used as eluant. The desiredproduct (0.22 g; 11%) is obtained in the form of an oil.

The above oil is dissolved in 5 ml of ethanol, and then a solution of0.11 g (0.0012 mol) of oxalic acid, dissolved in 5 ml of ethanol, isadded. The precipitate is filtered off and washed with cold ethanol.0.32 g of the desired product is obtained as a white solid.

Yield: 97%

Mp=76-83° C.

¹H-NMR (DMSO-d₆)δ(ppm): 7.6 (2H, m), 7.4 (1 H, m), 4.2 (2H, s), 3.3 (H,m), 3.0 ( H, m), 2.7 (H, m), 2.4 (H, m), 2.0 (H, m), 1.7 (H, m), 1.4 (H,m), 1.1 (H, m).

EXAMPLE 8 1-Aminopropylpyrroline

8.1-1-(2-Cyanoethyl)pyrroline

0.95 ml (0.0014 mol) of acrylonitrile is added, at 0° C., to a solutionof 1.00 g (0.0014 mol) of pyrroline in methanol. The mixture is stirredovernight at ambient temperature and is concentrated to dryness, to give1.65 g of the desired product in the form of an oil.

Yield: 93%

Mp=Oil

8.2-1-(3-Aminopropyl)pyrroline

0.024 g of 1M diisobutylaluminum hydride in toluene is added to asolution of 1.00 g (0.0089 mol) of 1-(2-cyanoethyl)pyrroline in 20 ml ofdichloromethane. The mixture is stirred overnight at ambienttemperature. The solution is treated with sodium sulfate decahydrate.The mixture is stirred for half an hour. The inorganic phases arefiltered and the filtrate is concentrated to dryness, so as to obtain1.00 g of a colorless oil.

Yield: 97%

Mp=Oil

¹H-NMR (CD₃Cl)δ(ppm): 5.75 (2H, s), 3.47 (4H, s), 2.75 (2H, t), 2.56(2H, t), 1.69 (2H, q).

The table below illustrates the chemical structures and the physicalproperties of some compounds according to the invention. The elementalmicroanalyses and the NMR, IR or mass spectra confirm the structures ofthe compounds obtained.

In the table, for the compounds of formula I, “Mp.” corresponds to themelting point.

TABLE 1 I

No. R2 —(C)n— R1 B Mp. (°C.) salt 1. H —(CH₂)₃— H —N(C₂H₅)₂  97–102Hydrochloride 2. H —(CH₂)₂— H

209–212 Hydrochloride 3. CH₃ —(CH₂)₃— H —N(C₂H₅)₂ 58–62 Oxalate 4. H—(CH₂)₃— CH₃ —N(C₂H₅)₂ amorphous Hydrochloride 5.

—(CH₂)₃— H —N(C₂H₅)₂ 91–95 Oxalate 6.

—(CH₂)₃— H —N(C₂H₅)₂  98–103 Oxalate 7.

—(CH₂)₃— H —N(C₂H₅)₂ 144–147 Oxalate 8. H —(CH₂)₃— H

65–70 Hydrochloride 9. H —(CH₂)₃— H

>250 Hydrochloride 10

—(CH₂)₃ H —N(C₂H₅)₂ 54–59 Oxalate 11.

—(CH₂)₃ H —N(C₂H₅)₂ 109–115 Oxalate 12. H —(CH₂)₃ H —N(C₂H₅)₂ 89–95Oxalate 13. H —(CH₂)₃— H

228–231 Hydrochloride 14.

—(CH₂)₃— H —N(C₂H₅)₂ 55–60 Oxalate 15.

—(CH₂)₂— H

142–148 Oxalate 16. —CH₃ —(CH₂)₃— H

 99–104 Oxalate 17. H —(CH₂)₃— H

244–249 Hydrochloride 18. H —(CH₂)₃— H

237–241 Hydrochloride 19. H —(CH₂)₃— H

238–245 Hydrochloride 20. H —(CH₂)₃— H —N(CH₃)₂ 230–234 Hydrochloride21.

—(CH₂)₃— H

130–141 Oxalate 22.

—(CH₂)₂— H

50–60 Oxalate 23.

—(CH₂)₂— H

77–82 Oxalate 24.

—(CH₂)₂— H

103–110 Oxalate 25.

—(CH₂)₂— H

106–109 Oxalate 26. H —(CH₂)₂— H

114–117 Hydrochloride 27. H —(CH₂)₂— H

115–117 Hydrochloride 28.

—(CH₂)₂— H

134–1 40 Oxalate 29.

—(CH₂)₂— H

133–138 Oxalate 30.

—(CH₂)₂— H

 86–110 Oxalate 31.

—(CH₂)₂— H

87–90 Oxalate 32.

—(CH₂)₂— H

66–77 Oxalate 33.

—(CH₂)₂— H

 80–107 Oxalate 34.

—(CH₂)₂— H

121–125 Oxalate

The compounds of the invention of formula I were subjected topharmacological assays which showed their advantage as active substancesin therapeutics.

More particularly, the compounds of the invention are histamineH₃-receptor antagonists. H₃ receptors are known to those skilled in theart and their advantage in therapeutics has been described in theliterature (“Histamine H₃ receptor antagonists” Exp. Opinion Ther.Patents (2000) 10 (7) :1045-1055). Thus, the compounds of the inventionof formula I were subjected to an in vitro affinity assay on the nativehistamine H₃ receptor in an adult rat brain membrane preparation, byspecific binding of [³H]—N-α-methylhistamine to this receptor, accordingto the methods described by A. Korte et al., in Biochem. Biophys. Res.Commun. 168, 979-986(1990) and by R. E. West Jr. et al., in Mol.Pharmacol. 38, 610-613(1990).

The K_(i) values for the compounds of the invention with respect to H₃receptors are between 0.1 nM and 5.0 μM, and, more particularly,(+/−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide(compound 15; Table 1) has a Ki of 0.3 nM.

The compounds of the invention of formula I were also subjected to acAMP formation assay, on the human histamine H₃ receptor transfectedinto CHO cells, by inhibition of the agonism caused by the specificbinding of R-α-methylhistamine to this receptor, according to themethods described by T. W. Lovenberg et al., in J. Pharmacol. Exp. Ther.293, 771-778(2000).

The IC₅₀ values for the compounds of the invention with respect to H₃receptors are between 0.1 nM and 5.0 μM.

By way of example, compound 15, included in Table 1, has an IC₅₀<10 nM,using an EIA kit (Amersham) to measure cAMP formation, on the humanhistamine H₃ receptor transfected into CHO cells, by inhibition of theagonism caused by the specific binding of R-α-methylhistamine to thisreceptor.

The compounds according to the invention have an activity that isselective for the histamine H₃ receptor. Effectively, the compounds havea Ki of greater than 7.0 μM in the in vitro affinity assay on the nativehistamine H₁ receptor in an adult rat brain membrane preparation byspecific binding of [³H]-pirilamine to this receptor, according to themethod described by Y. Q. Liu et al., in J. Pharmacol. Exp. Ther. 268,959 (1994).

Furthermore, the compounds of the invention of formula I were subjectedto in vivo tests showing their ability to reduce food intake in ratsfasting for 24 h.

The experiments were carried out on Wistar rats. The rats were placedindividually in transparent plastic cages 48×26, 5×21.5 cm. These cageswere placed in a room insulated against any noise, at a temperature of20 to 22° C., with a light cycle from 7 o'clock in the morning to 7o'clock in the evening, the rats having free access to water and to thefood.

Before the experiment was carried out, the rats were made to fast for 24h, with access, however, to water ad libitum. On the day of theexperiment, the carrier or the compound according to the presentinvention was administered i.p. or p.o., 15 or 30 minutes before a knownamount of food (30 g) was made available. Each hour, for 6 hours, theamount of food ingested by the rat was measured.

It was shown that the AD₅₀ values (mg/kg i.p. or p.o.) for the compoundsof the invention with respect to food intake may be less than 10. Forexample,(+/−)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide(compound 24; Table 1) decreases food intake by 54% during the firsthour after the i.p. administration of 10 mg/kg of the product.

The results of the tests show that the compounds of the invention makeit possible to reduce food intake in animals. Thus, they make itpossible to control weight gain, to treat obesity or to aid weight loss,in animals, but also in humans.

Thus, according to another of its aspects, a subject of the invention ismedicaments which comprise a compound of formula I or an addition saltof the latter with a pharmaceutically acceptable acid or else a hydrateor a solvate of the compound of formula I.

These medicaments find their use in therapeutics, in particular in thetreatment of pathologies in which a histamine H₃-receptor antagonistprovides a therapeutic benefit. In particular, such pathologies areobesity and diabetes. In addition, these compounds may be used in thetreatment of central nervous system diseases such as vigilance and sleepdisorders, narcolepsy, Alzheimer's disease and other dementias,Parkinson's disease, attention disorders in hyperkinetic children,memory and learning disorders, epilepsy, schizophrenia, moderatecognitive disorders, depression and anxiety. The states of depressionand anxiety include, for example, anxieties of anticipatory type (beforea surgical procedure, before a dental treatment, etc), anxiety caused byalcohol or drug dependency or withdrawal, mania, seasonal affectivedisorders, migraines and nausea. They can also be used in the treatmentof sexual dysfunction, dizziness and travel sickness.

The use of the compounds according to the invention for the preparationof a medicament for use in treating the pathologies mentioned above isan integral part of the invention.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active ingredient, at leastone compound according to the invention. These pharmaceuticalcompositions contain an effective dose of at least one compoundaccording to the invention, or a pharmaceutically acceptable salt, ahydrate or a solvate of said compound, and also at least one or morepharmaceutically acceptable excipients. Said excipients are chosenaccording to the pharmaceutical form and the method of administrationdesired, from the usual excipients that are known to those skilled inthe art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula I above, or possible salt, solvate orhydrate thereof, can be administered in unit administration form, as amixture with conventional pharmaceutical excipients, to animals or tohuman beings for the prophylaxis or the treatment of the disorders or ofthe diseases above.

The appropriate unit administration forms comprise oral administrationforms, such as tablets, soft or hard gelatin capsules, powders, granulesand oral solutions or suspensions, sublingual, buccal, intratracheal orintranasal administration forms, forms for administration by inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms, and implants. Fortopical application, the compounds according to the invention can beused in creams, gels, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, thedose of active ingredient can range between 0.1 μg and 50 mg per kg ofbodyweight and per day. Each unit dose can contain from 0.1 to 1000 mg,preferably from 1 to 500 mg, of active ingredient in combination with apharmaceutical excipient. This unit dose can be administered 1 to 5times a day so as to administer a daily dose of from 0.5 to 5000 mg,preferably from 1 to 2500 mg.

There may be specific cases were higher or lower dosages areappropriate. Such dosages also belong to the invention. According to theusual practice, the dosage appropriate for each patient is determined bythe physician according to the method of administration and the weightand response of said patient.

By way of example, a unit administration form of a compound according tothe invention:

Compound according to the invention 50.0 mg Mannitol 223.75 mg  Sodiumcroscaramellose  6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate  3.0 mg

According to another of its aspects, the present invention also relatesto a method of treating the pathologies indicated above, which comprisesthe administration, to a patient, of an effective dose of a compoundaccording to the invention or a pharmaceutically acceptable salt orhydrate or solvate thereof.

1. A compound of formula I:

in which: n represents a value from 1 to 6; —(C)n- represents a C₁₋₆ alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino and C₁₋₃ alkoxy; R1 represents a hydrogen atom, or a C₁₋₆ alkyl group; R2 represents a hydrogen atom, or a C₁₋₆ alkyl or C₃₋₆ cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, a monocyclic heteroaryl, and an aryl; the aryl being optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy and a C₁₋₃ alkylidenedioxy group; B represents NR3R4, wherein R3 and R4 represent, independently of one another, a C₁₋₆ alkyl group, or a hydrogen atom; or R3 and R4 together represent a C₁₋₆ alkylidene group, a C₂₋₈ alkenylidene group, a C₁₋₃ alkylidene-O—C₁₋₃ alkylidene group, or a C₁₋₃ alkylidene-N(R5)-C₁₋₃ alkylidene group where R5 represents a hydrogen atom, or a C₁₋₃ alkyl or C₁₋₆ alkylcarbonyl group, it being possible for these C₁₋₃ alkyl and C₁₋₆ alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C₁₋₃ alkoxy, nitro, cyano or amino group; or B represents an aminocycle, linked via a carbon to the group —NR1-(C)n-, said aminocycle being selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents selected from a phenyl, a benzyl, a halogen, a hydroxyl, a nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl and C₁₋₃ alkoxy group; the nitrogen atom being optionally substituted with a C₁₋₃ alkyl; or a salt, a hydrate or a solvate thereof; with the exclusion of the compound in which R₁ and R₂ represent hydrogen atoms, B represents a dimethylamino group and —(C)n- represents an ethylidene group.
 2. A compound as claimed in claim 1 wherein: n is equal to 2, 3 or 4; and R1 represents a hydrogen atom or a C₁₋₂ alkyl group; and R2 represents a hydrogen atom, or a C₁₋₄ alkyl or C₅₋₆ cycloalkyl group optionally substituted with 1 to 4 substituents selected from a phenyl, a C₃₋₆ cycloalkyl, C₁-₂ perhaloalkyl, C₁₋₃ haloalkyl and C₁₋₃ alkoxy; the phenyl being optionally substituted with 1 to 4 substituents selected from a halogen atom, hydroxyl, nitro, cyano, amino, C₁-₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy group and C₁₋₃ alkylidenedioxy; and B represents NR3R4, wherein R3 and R4 represent, independently of one another, a C₁₋₄ alkyl group; or when R3 and R4 together represent a C₁₋₆ alkylidene group, a C₂₋₈ alkenylidene group, a C₁₋₃ alkylidene-O—C₁₋₃ alkylidene group or a C₁₋₃ alkylidene-N(R5)-C₁₋₃ alkylidene group, B represents a group:

 or B represents an aminocycle linked via a carbon to the group —NR1-(C)n, chosen from aziridine, azetidine, pyrrolidine, piperidine and morpholine;  the groups R3, R4 and R5 and also the aminocycle being optionally substituted; or a salt, a hydrate or a solvate thereof.
 3. A compound as claimed in claim 2, wherein, when B represents NR3R4 and R3 and R4 together form a C₁₋₆ alkylidene group, a C₂₋₈ alkenylidene group, a C₁₋₃ alkylidene-O—C₁₋₃ alkylidene group or a C₁₋₃ alkylidene-N(R5)—C₁₋₃ alkylidene group, or when B represents an aminocycle, then B is selected from the group consisting of:

or a salt, a hydrate or a solvate thereof.
 4. A compound as claimed in claim 1, selected from the group consisting of: N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-(cyclohexylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-N-[3-(2-methylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(3,6-dihydropyridin-1(2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(diethylamino)propyl]-2-(3-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(4-benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-(cyclohexylmethyl)-N-(3-pyrrolidin-1ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(cyclopropylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-benzyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(1,3-benzodioxo1-5-ylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(4-bromobenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(2,5-dimethoxybenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(2-methylbutyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; (+/−)-2-(3-methoxybenzyl)-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; and (+/−)-2-(3,5-dimethylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, a hydrate or a solvate thereof.
 5. The compound according to claim 1 which is (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.
 6. The compound according to claim 1 which is (−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.
 7. A compound of formula I:

in which: n represents a value from 1 to 6; —(C)n- represents a C₁₋₆ alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂-₆ dialkylamino and C₁₋₃ alkoxy; R1 represents a hydrogen atom, or a C₁₋₆ alkyl group; R2 represents a C₁₋₆ alkyl or C₃₋₆ cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C₁-₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₃-₆ cycloalkyl, a monocyclic heteroaryl, and an aryl; the aryl being optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C₁-₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl, C₁₋₂ perhaloalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy and a C₁₋₃ alkylidenedioxy group; B represents NR3R4, wherein R3 and R4 represent, independently of one another, a C₁₋₆ alkyl group, or a hydrogen atom; or R3 and R4 together represent a C₁₋₆ alkylidene group, a C₂₋₈alkenylidene group, a C₁₋₃alkylidene-O—C₁₋₃alkylidene group, or a C₁₋₃ alkylidene-N(R5)-C₁₋₃ alkylidene group where R5 represents a hydrogen atom, or a C₁₋₃ alkyl or C₁₋₆ alkylcarbonyl group, it being possible for these C₁₋₃ alkyl and C₁₋₆ alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C₁₋₃ alkoxy, nitro, cyano or amino group; or B represents an aminocycle, linked via a carbon to the group -NR1-(C)n-, said aminocycle being selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents selected from a phenyl, a benzyl, a halogen, a hydroxyl, a nitro, cyano, amino, C₁₋₃ monoalkylamino, C₂₋₆ dialkylamino, C₁₋₃ alkyl and C₁₋₃ alkoxy group; the nitrogen atom being optionally substituted with a C₁₋₃ alkyl; or a salt, a hydrate or a solvate thereof.
 8. The compound according to claim 7 which is (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.
 9. The compound according to claim 7 which is (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.
 10. A compound selected from the group consisting of (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide and (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt of said compound; or a hydrate of said salt.
 11. A pharmaceutical composition containing a compound of formula I, as claimed in claim 1, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 12. A pharmaceutical composition comprising a compound according to claim 2, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 13. A pharmaceutical composition comprising a compound according to claim 3, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 14. A pharmaceutical composition comprising a compound according to claim 4, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 15. A pharmaceutical composition comprising a compound according to claim 5, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 16. A pharmaceutical composition comprising a compound according to claim 6, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 17. A pharmaceutical composition comprising a compound according to claim 7, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 18. A pharmaceutical composition comprising a compound according to claim 8, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.
 19. A pharmaceutical composition comprising a compound according to claim 9, or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient. 